Tyrosine phosphorylation is critical for the initiation of lymphocyte and myeloid cell activation. While much has been learned about the receptors and protein tyrosine kinases (PTKs) involved in initiating responses, less is known about the protein tyrosine phosphatases (PTPs) in regulating these pathways. PTPs are likely to help set activation thresholds and terminate responses. We have recently initiated studies on the function of CD148, a receptor-like PTP (RPTP), in the hematopoietic lineage. On T cells, CD148 expression is induced following T cell antigen receptor (TCR) stimulation. In the Jurkat cell line, induction of CD148 inhibits TCR signals, in part, via the dephosphorylation of the adaptor LAT and of phospholipase Cg1. CD148 is excluded from the immunologic synapse, suggesting that CD148 may play a key role in terminating TCR signals following disengagement of the T cell from an antigen-presenting cell. In contrast to T cells, CD148 is constitutively expressed on mouse B cells and myeloid cells. Little is known about the function of CD148 in these lineages. We have targeted the CD148 gene with loxP recombination sites flanking the exon of CD148 that encodes its transmembrane domain to study the effects of inactivation of CD148 expression on all cells as well as to be able to study the effects of lineage-specific inactivation of the gene. Our preliminary results suggest that CD148 positively regulates antigen and integrin receptor specific function in B cells and neutrophils, much like CD45 does. Here, we propose an integrated approach to study the apparently paradoxical distinct functions of CD148 in different hematopoietic lineages (i.e., T cells vs B and myeloid cells). We hypothesize that CD148 dephosphorylates important substrates in antigen, Fc receptor, and integrin pathways and plays critical but distinct roles in setting activation thresholds and in terminating antigen receptor signals that contribute to cell activation in each of these hematopoietic lineages. Specifically, we will: 1) characterize the developmental, functional, and biochemical consequences of CD148 loss on the T cell lineage, with emphasis on TCR signaling pathways; 2) characterize the developmental, functional and biochemical consequences of the loss CD148 on the B cell lineage, with emphasis on the antigen receptor signaling pathways; and, 3) characterize the biochemical, functional and immunological consequences of inactivating the CD148 gene in myeloid cells on integrin- and Fc-receptor dependent pathways.